Yamada Yoshihiro, Zhong Yi, Miki Shiho, Taura Akiko, Rabbitts Terence H
The Central Biomedical Laboratory, Aino University School of Health Science, 4-5-11 Higashi-ohta, Ibaraki, Osaka, 567-0012, Japan.
David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan-Kettering Cancer Center, 417 East 68th Street, New York, NY, 10065, USA.
Sci Rep. 2022 May 4;12(1):7226. doi: 10.1038/s41598-022-11297-3.
The transcription factor complex, consisting of LMO2, TAL1 or LYL1, and GATA2, plays an important role in capillary sprouting by regulating VEGFR2, DLL4, and angiopoietin 2 in tip cells. Overexpression of the basic helix-loop-helix transcription factor LYL1 in transgenic mice results in shortened tails. This phenotype is associated with vessel hyperbranching and a relative paucity of straight vessels due to DLL4 downregulation in tip cells by forming aberrant complex consisting of LMO2 and LYL1. Knockdown of LMO2 or TAL1 inhibits capillary sprouting in spheroid-based angiogenesis assays, which is associated with decreased angiopoietin 2 secretion. In the same assay using mixed TAL1- and LYL1-expressing endothelial cells, TAL1 was found to be primarily located in tip cells, while LYL1-expressing cells tended to occupy the stalk position in sprouts by upregulating VEGFR1 than TAL1. Thus, the interaction between LMO2 and TAL1 in tip cells plays a key role in angiogenic switch of sprouting angiogenesis.
由LMO2、TAL1或LYL1以及GATA2组成的转录因子复合物，通过调节顶端细胞中的VEGFR2、DLL4和血管生成素2，在毛细血管生成中发挥重要作用。在转基因小鼠中，碱性螺旋-环-螺旋转录因子LYL1的过表达导致尾巴缩短。这种表型与血管过度分支以及由于顶端细胞中DLL4下调导致的直血管相对较少有关，DLL4下调是通过形成由LMO2和LYL1组成的异常复合物实现的。在基于球体的血管生成试验中，敲低LMO2或TAL1会抑制毛细血管生成，这与血管生成素2分泌减少有关。在使用表达TAL1和LYL1的混合内皮细胞的相同试验中，发现TAL1主要位于顶端细胞，而表达LYL1的细胞通过比TAL1上调VEGFR1，倾向于占据新芽中的茎干位置。因此，顶端细胞中LMO2和TAL1之间的相互作用在发芽血管生成的血管生成开关中起关键作用。
